IGSF11-VISTA is a critical and targetable immune checkpoint axis in diffuse midline glioma
Summary
Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with no curative treatment, and lacks a comprehensive understanding of immune-tumor cell interactions within their spatial context. Our multi-omics approach, integrating single-nuclei RNA sequencing, spatial transcriptomics, and high-dimensional imaging, utilizes patient samples and an experimental murine DMG model to unveil two spatially distinct regions. MES-patterns are defined by mesenchymal (MES) tumor cells and blood-derived immune cells, whereas AOO-patterns are enriched with astrocyte (AC)-, oligodendrocyte (OC)-, and oligodendrocyte precursor cell (OPC)-like cancer populations, alongside homeostatic-like microglia. The less-studied immune checkpoint, IGSF11, is primarily expressed by AOO-associated cancer cells, while its receptor VISTA is detected mainly in homeostatic microglia. Targeting IGSF11-VISTA results in tumor reduction and survival benefit, mediated by brain-resident microglia and independent of T cell infiltration. This positions IGSF11-VISTA as a promising immune checkpoint treatment axis to harness the local brain immune response against DMG. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
| Authors | Collot R, Ruiz-Moreno C, Honhoff C, van den Broek TJM, Wezenaar AKL, Kloosterman DJ, Ariese HCR, Johnson H, Vervoort BMT, Jeiroshi A, Bunt J, van Ineveld RL, Bokobza E, Rebel HG, Te Pas BM, Ringnalda FCA, van de Wetering M, Robe PA, Kool M, Cochran JR, Kranendonk MEG, van Vuurden DG, Hulleman E, Wehrens EJ, Zomer A, Stunnenberg HG, Rios AC |
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| Journal | Cancer cell |
| Publication Date | 2026 Mar 9;44(3):641-657.e9 |
| PubMed | 41576930 |
| PubMed Central | PMC12994606 |
| DOI | 10.1016/j.ccell.2025.12.020 |